US3417085A - 3,1-benzothiazines and 3,1-benzoxazines - Google Patents

3,1-benzothiazines and 3,1-benzoxazines Download PDF

Info

Publication number
US3417085A
US3417085A US552416A US55241666A US3417085A US 3417085 A US3417085 A US 3417085A US 552416 A US552416 A US 552416A US 55241666 A US55241666 A US 55241666A US 3417085 A US3417085 A US 3417085A
Authority
US
United States
Prior art keywords
grams
phenyl
chloro
amino
benzothiazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US552416A
Other languages
English (en)
Inventor
Kuch Heinz
Seidl Gunther
Hoffmann Irmgard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Application granted granted Critical
Publication of US3417085A publication Critical patent/US3417085A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/02—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with only hydrogen, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/14—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2

Definitions

  • the present invention provides heterocyclic compounds and a process for preparing them; more particularly, the present invention provides new derivatives of 3,1-benzothiazine and 3,1-benzoxazine which have valuable pharmacological properties and which correspond to the general Formula I /N ⁇ NHR R,
  • A oxygen or sulfur
  • R is hydrogen, alkyl of l to 6 carbon atoms, cyclohexyl, lower alkenyl, cycloalkenyl of five to six carbon atoms, phenyl, benzyl, dilower alkylamino-lower alkyl, piperidino-lower alkylene, morpholino-lower alkylene, pyrrolidino-lower alkylene, N-lower alkyl-piperazino-lower alkylene or N-benzylpiperazino-lower alkylene;
  • R is hydrogen, halogen, methoxy, trifluoromethyl or nitro;
  • R is lower alkyl, benzyl, unsubstituted aryl of 6 to 10 carbon atoms, or phenyl substituted by halogen, methoxy, trifiuoormethyl or nitro, or acid addition salts of said compounds with a physiologically compatible organic or inorganic acid.
  • the compounds of the present invention and their salts with inorganic and organic acids can be obtained by (a) Reacting, if necessary with the addition of acids and/ or water-separating agents, compounds of the general Formula II B2 II in which R and R have the meanings given above and X represents a chlorine or bromine atom, a hydroxyl, sulfhydryl, alkoxy, alkylthio or alkanoyloxy group, with thioureas of the general Formula 111a in which R has the meaning given above and the two rad- 3,417,085 Patented Dec.
  • I968 "ice icals R may be identical or different, or with isothiocyanates of the general Formula IIIb in which R has the meaning given above, or with compounds which form such isothiocyanates, or by reacting compounds of the Formula II in which X represents a chlorine or bromine atom, a hydroxyl, alkoxy or alkanoyloxy group, with isocyanates of the general Formula 1110 in which R has the meaning given above, or with compounds which form such isocyanates, if necessary with the addition of acids and/ or water-separating agents, or
  • Y represents a chlorine, bromine or iodine atom, if necessary, with subsequent acid treatment, or
  • Z-amino-benzhydrols there may be used as starting substances of the general Formula II, for example, Z-amino-benzhydrols.
  • the lower O-alkyl ethers which corrmpond to the above-mentioned benzohydrols for example, 2-amino-benzohydryl-methyl ether, Z-aminobenzohydryl-ethyl ether, or the corresponding esters with low molecular weight aliphatic carboxylic acids, for example, the acetates or propionates of the afore-mentioned benzohydrols.
  • corresponding halides such as 2-aminophenyl-phenyl-chloro- (or bromo-) methane and the compounds which are correspondingly substituted in the phenyl radicals, for the preparation of benzothiazine also the corresponding mercaptanes and lower alkylthioethers such as 2-amino-phenylphenylmethylmercaptane or the corresponding lower alkyl thioethers may also be used.
  • a-methyl- 2-aminobenzyl alcohol a-methyl-2-amino-fiuorobenzyl alcohols, a-methyl-Z-aminochlorobenzyl alcohols, a-methyl- 2-amino-bromobenzyl alcohols, a-methyl 2 amino-methoxy-benzyl alcohols, a-methyl-Z-amino-trifiuoromethylbenzyl alcohols, wmethyI-Z-amino-nitmbenzyl alcohols, a-ethyl-2-aminobenzyl alcohol, methyl-2-aminochlorobenzyl alcohols, ot-ethyl-Z-aminomethoXy-benzyl alcohols, OL- ethyl-Z-amino-trifluoromethyl-benzyl-alcohols, wethyl-Z- amino-nitrobenzyl alcohols, ot-propyl-2-aminobenz
  • the low molecular weight O-alkyl ethers which correspond to the above-mentioned benzyl-alcohols or the corresponding esters with lower aliphatic carboxylic acids, for example, the acetates or propionates of the mentioned benzyl alcohols.
  • corresponding halides such as methyl-2-aminophenylchloro- (or -bromo-) methane or the compounds which are correspondingly substituted in the phenyl radical
  • benzothiazines also the corresponding mercaptanes and low molecular weight alkyl thioethers such as a-methyl-2-amino-benzyl-mercaptan, or the corresponding low molecular weight alkyl thioethers may likewise be used.
  • salts derived from the said basic compounds with strong acids such as hydrohalic acids, sulfuric acid as well as benzeneand toluene-sulfonic acid are likewise suitable as starting substances.
  • thiourea and the N-monoor N,N'- di-substituted derivatives thereof such as N-methyl-, N- ethyl-, N-propyl-, N-isopropyl-, N-butyl-, N-isobutyl-, N- hexyl-, N-cyclohexyl-, N-allyl-, N-cyclohexenyl-, N-phenyl-, N-benzyl-, N-diethyl-aminoethyl-, N-dimethyl-aminopropyl-, N,N'-dimethyl-, N,N-diethyl-thiourea, whereas as starting substances of the general Formula IIIb, there may be used isothioisocyanates such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-,
  • isocyanic acid and isocyanates such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, hexyl-, cyclohexyl-, allyl-, cyclohexenyl-, phenyl-, benzyl-, dimethylaminopropyl-isocyanate; furthermore, there may be used substances which form such isocyanates (cf. Houben Weyl, Methoden der organischen Chemie, 4th edition, volume 8, pages 119-127) and the corresponding carbamic acid chlorides and urethanes.
  • isocyanic acid and isocyanates such as methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, hexyl-, cyclohexyl-, allyl-, cyclohexenyl-, phenyl-, benzy
  • reaction of the compounds of the general Formula II as well as of their acid addition salts with thioureas of the general Formula IIIa according to (a) is carried out at temperatures in the range of 20 to 250 C., preferably to 180 C.
  • the reaction is carried out in the presence of inorganic or organic acid, for example hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, furthermore sulfuric acid, phosphoric acid, lower aliphatic carboxylic acids such as formic acid and acetic acid, halogeno-carboxylic acids such as chloroacetic acid, trifluoroacetic acid or benzeneand toluenesulfonic acid, or mixtures thereof.
  • hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid
  • sulfuric acid sulfuric acid
  • phosphoric acid lower aliphatic carboxylic acids
  • lower aliphatic carboxylic acids such as formic acid and acetic acid
  • halogeno-carboxylic acids such as chloroacetic acid, trifluoroacetic acid or benzeneand toluenesulfonic acid, or mixtures thereof.
  • the reaction may also be carried out, if necessary, in the presence of water-separating agents, for example, inorganic acid halides and acid anhydrides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, thionyl chloride or phosphorus pentoxide, and zinc chloride or boron fluoride.
  • water-separating agents for example, inorganic acid halides and acid anhydrides such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, thionyl chloride or phosphorus pentoxide, and zinc chloride or boron fluoride.
  • reaction of compounds of the general Formula II with the compounds of the general Formulae 11112 and 111a is carried at temperatures in the range of O to 200 0., preferably 130 C.
  • Intermediately formed urea or thiourea derivatives which, if desired, can be isolated as intermediate products, are converted into the products of the invention by a subsequent treatment of the reaction mixture or of the isolated intermediate compounds With inorganic or organic acids or with agents splitting-01f Water; the use of elevated temperatures, depending on the speed of the reaction, may be of advantage.
  • solvents or diluents there may be used, if desired or if necessary, Water, lower alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofurane, dioxane, furthermore glycol, glycol monomethylandethyl ether, diand tri-ethylene glycol, as well as aromatic hydrocarbons such as benzene, toluene, xylene or chlorohydro-carbons such as chlorobenzene, chloroform, trichlorethylene or tetrachlorethane; the selection of the suitable solvent or diluent depends on the stability and reactivity of the reaction components used.
  • lower alcohols such as methanol, ethanol, isopropanol
  • ethers such as diethyl ether, tetrahydrofurane, dioxane, furthermore glycol, glycol monomethylandethyl ether, diand tri-ethylene
  • reaction times may be varied within Wide limits according to the reactivity of the components and the temperature chosen.
  • the reaction products of the general Formula I which in most cases are obtained in the form of salts may be isolated directly, if required after concentration of the solution, and, if desired, converted into the free bases by subsquent treatment with alkali. It is also possible to adjust the pH of the reaction mixture to an alkaline value prior to the isolation, whereby the reaction products can be isolated in the usual manner in the form of the free bases.
  • the functional derivatives of these ureas for example compounds which contain instead of the urea grouping the pre-stages thereof such as the carbodiimide group, the guanidino or the chloroformic acid amidine group, may also be used for the reaction according to (b) to obtain the products of the invention.
  • This reaction is carried out at temperatures in the range of 50 to 200 C., preferably 80 to 160 C., if necessary with the addition of acids and in the presence of an organic solvent, for example, an aromatic hydrocarbon such as benzene, toluene or xylene or an aliphatic or aromatic chlorohydrocarbon such as carbon tetrachloride, tetrachloroethane or chlorobenzene.
  • an organic solvent for example, an aromatic hydrocarbon such as benzene, toluene or xylene or an aliphatic or aromatic chlorohydrocarbon such as carbon tetrachloride, tetrachloroethane or chlorobenzene.
  • pyridine is particularly advantageous, however, the use of pyridine as the solvent.
  • the reaction is carried out under pressure, if necessary.
  • Ureas of the general Formula IV in which X stands for the sulfhydryl group may also be converted into the products of the invention by treatment with dehydrating agents such as inorganic acid halides and acid anhydrides.
  • isothiocyanate there may be used methyl-, ethyl-, propyl-, isopropyl, butyl-, isobutyl-, hex'yl-, cyclohexyl-, allyl-, cyclopentenyl-, phenyl-, benZyl-, dimethylaminoethyl-, piperidinoethyl-, morpholinoethyl-, N- methylpiperazinoethy1-, diethylaminopropyl-, pyrrolidinopropyl-, morpholinopropyl-, N-benzyl-piperazinopropylisothiocyanate.
  • isothiocyanates there may also be used substances which form such isothiocyanates (cf. Houben-Weyl, Methoden de organischen Chemie, 4th edition, volume 9, pages 867-878) and the corresponding thiourethanes or dithiocarbamic acid esters.
  • the desulfurization of the thio-ureas of the general Formula IV is effected by the reaction with desulfurizing agents such as heavy metal oxides or heavy metal salts, for example, mercury oxide, silver oxide, lead oxide, arsenic trioxide, lead acetate, silver nitrate, mercury chloride or with oxidizing agents such as sodium hypochlorite.
  • desulfurizing agents such as heavy metal oxides or heavy metal salts, for example, mercury oxide, silver oxide, lead oxide, arsenic trioxide, lead acetate, silver nitrate, mercury chloride or with oxidizing agents such as sodium hypochlorite.
  • Carbodiimides which are formed intermediately are in general not isolated, since they pass under the reaction conditions, for example, in the case of compounds of the general Formula IV in which X represents the hydroxy group, into the compounds of the invention, whereas in the case of compounds of the general Formula IV in which X represents an alkoxy or alkanoyloxy group, it is necessary to treat the intermediate subsequently or simultaneously with inorganic or organic acids.
  • the reaction is carried out at temperatures in the range of from 20 to 200 C., preferably 50 to 120 C.; the reaction times vary between 15 minutes and 30 hours.
  • reaction medium there may be used water, lower alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofurane, dioxane, furthermore glycol, glycol monomethyl and -ethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, chlorohydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethylene or acetone or carbon disulfide, or mixtures thereof; the selection of the suitable solvent depends on the stability and the reactivity of the individual reaction components and reaction products.
  • lower alcohols such as methanol, ethanol, isopropanol
  • ethers such as diethyl ether, tetrahydrofurane, dioxane, furthermore glycol, glycol monomethyl and -ethyl ether, aromatic hydrocarbons such as benzene, toluene,
  • the compounds of the general Formula V which are required as starting substances for the reaction according to (b) with the amines of the Formula VI or the salts thereof, can be prepared, for example, by reacting according to (a) compounds of the Formula II with thiourea. In this manner compounds of the Formula V are obtained in which R represents the amino group.
  • compounds of the general Formula II in which X stands for a halogen atom the hydroxy, sulfhydryl or an alkanoyloxy group, are reacted with carbon disulfide or alkali xanthogenates in the presence of bases such as alkali metal hydroxides (for example, in a manner analogous to that described in J. Pharm. Soc.
  • the mercapto compounds obtained may be alkylated, if required or desired, whereby R obtains the meaning of the S-alkyl group.
  • the compounds of the general Formula V in which R represents a chlorine or a bromine atom are accessible, for example, from compounds of the general Formula V in which R represents the amino group by way of the Sandmeyer reaction (for example, in a manner analogous to that described in Helv. Chim.
  • solvents there may be used mainly aromatic hydrocarbons such as benzene, toluene and xylenes, aliphatic and aromatic chlorohydrocarbons such as chloroform, tetrachloroethane, chlorobenzene, furthermore ethers such as tetrahydrofurane, dioxane, glycol dimethyland diethylene glycol diethyl ethers; in addition, an excess of the amine used may also serve as solvent. Depending on the boiling point of the amine used and of the solvent, the reaction is carried out in a closed vessel, if necessary.
  • aromatic hydrocarbons such as benzene, toluene and xylenes
  • chlorohydrocarbons such as chloroform, tetrachloroethane, chlorobenzene
  • ethers such as tetrahydrofurane, dioxane, glycol dimethyland diethylene glycol diethyl ethers
  • alcohol derivativesl especially the halides such as chlorides, bromides or iodides, furthermore the corresponding sulfates, carbonates and alkyl or aryl sulfonates of these alcohols, for example, methyl iodide, dimethyl sulfate, ethyl iodide, benzyl bromide, allyl bromide, dimethylaminoethyl chloride, piperidinopropyl chloride, bis-(diethylaminoethyl carbonate), ethyl-toluene sulfonate.
  • the alkylation is carried out in the usual manner in the presence of basic condensation agents such as alkali metal carbonates and hydroxides, alkali metal alcoholates, alkali metal
  • derivatives of 2-acylamino-benzothiazine or -benzoxazine which may be substituted by the groups R and R for example, the corresponding aliphatic acylamino derivatives such as 2-acetylamino-, 2-propiOnylamino-, 2-butyrylamino-, 2-crotonylamino-4- phenyl-4H-3,l-benzothiazine or -benzoxazine or aromatic acylamino derivatives such as the 2-benzoylamino-4- phenyl-4H-3,l-benzothiazine or -benzoxazine derivatives.
  • the groups R and R for example, the corresponding aliphatic acylamino derivatives such as 2-acetylamino-, 2-propiOnylamino-, 2-butyrylamino-, 2-crotonylamino-4- phenyl-4H-3,l-benzothiazine or -benzoxazin
  • Halogenated aliphatic acyl compounds for example, 2 chloroacetyl-, 2 chloropropionyl-, 2 chlorobutyryl- 4-phenyl-4H-3,l-benzothiazine or -benzoxazine derivatives may also be used.
  • acyl compounds are prepared in the usual manner by acylation of the Z-aminobenzothiazineor oxazine derivatives, for example, by reaction of acid chlorides such as acetyl chloride, propionyl chloride, crotonyl chloride or of the corresponding anhydrides such as acetic acid anhydride, propionic acid anhydride, with Z-amino- 4-phenyl-4H-3,l-benzothiazines or -benzoxazines which may be substituted by R and R
  • the acyl compounds, especially the halogenated acyl compounds can also be obtained by reaction of these Z-aminobenzothiazine or -benzoxazine derivatives with the corresponding carboxylic acids in the presence of a dehydrating agent, for example, dicyclohexylcarbodiimide.
  • Starting substances basically substituted acyl compounds such as 2-dialkylaminoacetylor 2-dialkylaminopropionyl-amino-4-phenyl- 4H-3,1-benzothiazine or -benzoxazine derivatives, the dialkylamino group being low molecular Weight dialkylamino groups, preferably dimethylor diethylamino groups, and the corresponding piperidino-, pyrrolidino-, N-methyl-piperazino, morpholinoor N-benzyl-piperazinoacylamino-4-phenyl-4H-3,l-benzothiazine or -benzoxazine derivatives.
  • substituted acyl compounds such as 2-dialkylaminoacetylor 2-dialkylaminopropionyl-amino-4-phenyl- 4H-3,1-benzothiazine or -benzoxazine derivatives
  • the dialkylamino group being low molecular Weight dialkyla
  • the reduction of the acyl derivatives is carried out according to the process of the invention in the usual manner with complex metal hydrides, in particular with lithium aluminum hydride, in inert solvents, preferably ethers such as dioxane, ether, tetrahydrofurane, if desired in admixture with aromatic hydrocarbons at temperatures in the range of from C. to the boiling temperature of the solvent used.
  • complex metal hydrides in particular with lithium aluminum hydride
  • inert solvents preferably ethers such as dioxane, ether, tetrahydrofurane, if desired in admixture with aromatic hydrocarbons at temperatures in the range of from C. to the boiling temperature of the solvent used.
  • ll halogeno-acy] compounds are used, these may be either reacted with the corresponding amines such as dimethylamine, diethylamine, dipropylamine or with the corresponding heterocyclic amines such as piperidine, pyrrolidine, morpholine, N-methylpiperazine or N-benzylpiperazine or they may be first reduced in the manner described and the halogeno-alk-yl compounds obtained are then reacted in the usual manner with the described amines. In this reaction it is of advantage to use an excess of the amine for binding the hydrohalic acid formed.
  • reaction of compounds of the general Formula II with halogeno cyanides according to (f), which leads to benzoxazines exclusively, is preferably carried out in the presence of weak bases, for example, alkali metal or alka line earth metal salts of fatty acids such as sodium ace tate, alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides, at temperatures in the range of from 20 to C. and reaction times from 30 minutes to 30 hours.
  • weak bases for example, alkali metal or alka line earth metal salts of fatty acids such as sodium ace tate, alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides
  • solvents and diluents there may be used, for example, lower alcohols such as methanol, ethanol, isopropanol, ethers such as diethyl ether, tetrahydrofurane, dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, chlorohydrocarbons such as methylene chloride, chlorform, dichloroethane, chlorobenzene, furthermore acetone and pyridine, or mixtures of these solvents.
  • lower alcohols such as methanol, ethanol, isopropanol
  • ethers such as diethyl ether, tetrahydrofurane, dioxane
  • aromatic hydrocarbons such as benzene, toluene, xylene
  • chlorohydrocarbons such as methylene chloride, chlorform, dichloroethane, chlorobenzene, furthermore acetone and pyridine, or mixtures of these solvent
  • benzothiazines of the Formula I there is also suitable the process described under (g).
  • A represents an oxygen atom
  • reaction of these compounds with hydrogen sulfide or inorganic sulfides such as alkali metal sulfides or phosphorus sulfides, preferably phosphorus pentasulfide, or With mixtures of these compounds is effected at temperatures in the range of from 50 to 200 C., preferably 80 to C., if desired with the use of an organic solvent such as pyridine, an aromatic hydrocarbon such as benzene, toluene, or xylene, or an aliphatic or aromatic chlorohydrocarbon such as carbon tetrachloride, tetrachloroethane or chlorobenzcne.
  • an organic solvent such as pyridine, an aromatic hydrocarbon such as benzene, toluene, or xylene, or an aliphatic or aromatic chlorohydrocarbon such as carbon tetrachloride, tetrachloroethane or chlorobenzcne.
  • the reaction may be carried out under pressure,
  • the products of the present invention are basic compounds and they, therefore, can be converted into the corresponding salts with the aid of inorganic or organic acids.
  • inorganic acids there may be used, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid and amidosulfonic acid.
  • organic acids there may be used, for example, acetic acid, propionic acid, lactic acid, glycolic acid,
  • glutonic acid fumaric acid, maleic acid, oxalic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, aceturic acid, oxyethane-sulfonic acid and ethylene diamino-tetracetic acid, embonic acid, naphthalene-disulfonic acid or toluene-sulfonic acid.
  • the products of the present invention have valuable pharmacological properties with partly extremely low toxicity; in particular, they have a centrally depressive as well as a stimulating, tranquillizing, noradrenalin activating and anesthesia prolonging and, in addition, analgesic and spasmolytic activity.
  • the other properties by which the products of the present invention are distinguished include anesthesia-prolonging properties and the increase of the physiologic action of the catecholamines as well as anticataleptic effects which correspond to the thymoleptic action in humans.
  • the centrally depressive action was determined by measuring the spontaneous and provoked motility in a mouse and by the somnolence test (Nieschulz, O. et al., Arzneiffenforschung 6, 651 (1956)); the influence on anesthesia was determined in the usual manner. Breaking through or unblocking of catalepsy in a mouse produced by 2 oxo 3 isobutyl 9,10, dimethoxy 1,2,3,4,6,7- hexahydro 11 b H benzo[a] quinolizine (tetrabenazine) was tested on a modification of the test arrangement described by Sulser et al. (Fed. Proc. 19, 268 (1960), and in Ann. NY. Acad. Sci. 96, 279 (1962)). The test for noradrenalin potentiating action was carried out on the blood pressure of a cat.
  • the products of the present invention may be applied as such or in the form of corresponding salts, if desired in admixture with pharmaceutically usual carrier substances.
  • the pharmaceutical preparations may he in the form of tablets, drages, capsules or suppositories, or they may be in liquid form, for example, in the form of solutions, suspensions or emulsions.
  • the tablets, drages and capsules may have a total weight ranging from 100 to 1000 mg., and their content of active substance may be in the range of from 5 to 50 mg., thus 0.5 to 50% by weight.
  • the preparations can be administered several times a day.
  • the pharmaceutically usual carrier substances there may be used those substances which do not react with the products of the invention, for example, water, gelatin, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, and similar substances. They may be sterilized and/or combined with stabilisers.
  • the pharmaceutical preparations may also contain other therapeutically valuable substances.
  • the products of the present invention serve for the treat ment of psychical diseases and disorders, for example, depressions, psychoneuroses, discords and anxiety of neurotic and psychotic genesis.
  • the above hydrobromide need not be isolated.
  • the reaction mixture is diluted with a quantity of water suflicient for dissolving the salt and rendered alkaline with dilute sodium hydroxide solution.
  • EXAMPLE 12 26.8 grams of 5,4'-dichloro-2-amino'benzhydr0l (melting point -131 C. (from methanol/water), prepared from 5,4'-dichloro-2-aminobenz0phenone by reduction with sodium boron hydride) and 7.6 grams of thiourea are heated for 2 hours under reflux, while stirring, in a solution of 37.7 grams of p-toluenesulfonic acid in 60 milliliters of water. After cooling, the reaction mixture is rendered alkaline by means of dilute sodium hydroxide solution and extracted with benzene.
  • EXAMPLE 14 2-ethylamino-4-phenyl-4I-I-3 1 -benzothiazine (a) 20 grams of Z-aminobenzhydrol and 13 grams of ethyl-isothiocyanate are heated for minutes to 90 C. and then rapidly cooled. The reaction mixture is digested with ether, the crystal magma that has formed is filtered with suction and afterwashed with a small amount of ether; in this manner 23 grams (80% of the theory) of N-ethyl-N-[2-(a-hydroxybenzyl) ]-phenyl-thiourea in the form of colorless crystals which melt at 120122 C. are obtained.
  • EXAMPLE 16 (a) 35 grams of 5-chloro-2-amino-benzhydrol are dissolved in just the sufficient amount of ether, 30 grams of isopropylisothiocyanate are added and the reaction mixture is allowed to stand for several days at room temperature. Two-thirds of the solvent are then distilled off under reduced pressure and the crystalline precipitate is isolated by filtration with suction and after-washing with a small amount of ether. In this manner there are obtained 40 grams of the theory) of pure N-isopropyl-N-[4- chloro-2-(a-hydroxybenzyl)]-phenylthiourea which melts at 127129 C.
  • EXAMPLE 17 23 grams of 5-chloro-2-amino-benzhydrol are heated together with 20 grams of propyl-isothiocyanate for 15 minutes on the steam bath and rapidly cooled to room temperature. The crystal magma that has formed during standing of the reaction mixture over night is filtered with suction and after-washed with a small amount of a mixture of ether and petroleum ether in the ratio of 1:1; 28.5 grams (85% of the theory) of N-propy1-N'-[4-chloro-2-(a-hydroxybenzyl)]-phenyl thiourea in the form of colorless crystals melting at 96-98" C. are obtained.
  • EXAMPLE 18 (a) A solution of 25 grams of 2-amino-5-ch1oro-2'- fluorobenzhydrol (melting point 99100 0, prepared from 2-amino-5-chloro-2'-fluorobenzophenone by reduction with sodium boron hydride) in 250 milliliters of ether is combined with 13 grams of ethyl-isothiocyanate and the reaction mixture is stored for several days at room temperature.
  • EXAMPLE 28 2-cyclohexylamino-4-methyl-4H- 3 l-benzothiazine 27.8 grams of N-cyclohexyl-N-[2-(a-hydroxyethyl)]- phenyl thiourea (melting point 143-145 C., from a mixture of ethyl acetate and petroleum ether) obtained in a yield of 83% by the reaction of 2-amino-a-methyl-benzyl alcohol with cyclohexyl-isothiocyanate according to Example 26 (a), are heated for 45 minutes under reflux, while stirring, in milliliters of hydrobromic acid having a strength of 48%.
  • EXAMPLE 39 2-methylamino-4-phenyl-6-chloro-4H-3,l-benzoxazine
  • Example 38(b) there are obtained from 31 grams of N-methyl- N- [4-chloro-2- ot-hydroxybenzyl) ]-phenyl-thiourea prepared according to the method described in Example 5(a), 21 grams (77% of the theory) of 2-methylamino-4- phenyl-6-chloro-4H-3,l-benzoxazine melting at 149150 C. (from a mixture of benzene and petroleum ether).
  • the free base can be obtained by shaking the oxalate with methylene chloride and dilute sodium hydroxide solution and concentrating the organic phase; after recrystallization from a mixture of benzene and petroleum ether, the base melts at 133l34 C.
  • EXAMPLE 46 24 grams of the 2-(w-ethyl-thioureido) 5,4'-dichlorobenzhydrol described in Example 17 are treated with mercury oxide according to the method described in Example (b). After recrystallization of the crude product from a mixture of benzene and petroleum ether, there are obtained 12.5 grams (60% of the theory) of 2-ethylamino- 4-(p-chlorophenyl)-6-chloro-4H-3,l-benzoxazine melting at 144145 C.
  • EXAMPLE 47 15 grams of N-ethyl-N' [4 chloro 2 (a hydroxybenzyl)]-phenyl-urea (melting point 130-132 C., prepared according to Example are heated for 5-10 minutes, while stirring, on the steam bath with 50 milliliters of hydrobromic acid having a strength of 48% and then rapidly cooled. After working up according to Example 41(b), there are obtained 12.5 grams (88% of the theory) of 2-ethylamino-4-phenyl-6-chloro-4H 3,1 benzoxazine melting at 124-125 C.
  • A is oxygen or sulfur
  • R is hydrogen, alkyl of 1 to 6 carbon atoms. cyclohexyl, lower alkenyl, cycloalkenyl of five to six carbon atoms, phenyl, benzyl, dilower alkylamino-lower alkyl, piperidino-lower alkylene, morpholinolower alkylene, pyrrolidino-lower alkylene, N-lower alkyl-piperazino-lower alkylene or N-benzyl-piperazinolower alkylene; R is hydrogen, halogen, methoxy, trifluoromethyl or nitro; R is lower alkyl, benzyl, unsubstituted aryl of 6 to 10 carbon atoms, or phenyl substituted by halogen, methoxy, trifluoromethyl or nitro, or an acid addition salt of said compound with a physiologically compatible organic or inorganic acid.
  • R is an alkyl of l to 3 carbon atoms.
  • R means References Cited UNITED STATES PATENTS 3,168,517 2/1965 Behner et a1. 260243 OTHER REFERENCES Sharma et al.: J. Org. Chem, vol. 28, pp. 7402 (1963).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Check Valves (AREA)
US552416A 1965-06-03 1966-05-24 3,1-benzothiazines and 3,1-benzoxazines Expired - Lifetime US3417085A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DEF0046229 1965-06-03
DEF0048687 1966-03-18
DEF0048726 1966-03-22
DEF0048739 1966-03-23
DEF0048738 1966-03-23

Publications (1)

Publication Number Publication Date
US3417085A true US3417085A (en) 1968-12-17

Family

ID=27512066

Family Applications (1)

Application Number Title Priority Date Filing Date
US552416A Expired - Lifetime US3417085A (en) 1965-06-03 1966-05-24 3,1-benzothiazines and 3,1-benzoxazines

Country Status (11)

Country Link
US (1) US3417085A (en))
BE (1) BE682070A (en))
BR (1) BR6680180D0 (en))
CH (1) CH496724A (en))
DE (5) DE1545820A1 (en))
ES (1) ES327432A1 (en))
FR (2) FR5710M (en))
GB (1) GB1152486A (en))
IL (1) IL25858A (en))
NL (1) NL6607386A (en))
NO (1) NO119681B (en))

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3502666A (en) * 1966-11-26 1970-03-24 Hoechst Ag 3,1-benzothiazine derivatives
US3725404A (en) * 1966-11-24 1973-04-03 Hoechst Ag 2-amino-4,4-di-substituted-4h-3,1-benzoxazines
US4002622A (en) * 1975-10-30 1977-01-11 Morton-Norwich Products, Inc. 2-(3-Chloroanilino)-4H-3,1-benzothiazine
US4002621A (en) * 1975-10-30 1977-01-11 Morton-Norwich Products, Inc. 6-Chloro-2-(3,4-dichloroanilino)-4H-3,1-benzothiazine
US4002620A (en) * 1975-10-30 1977-01-11 Morton-Norwich Products, Inc. 2-Anilino-4H-3,1-benzothiazines
US4005082A (en) * 1967-09-25 1977-01-25 Gruppo Lepetit S.P.A. 1H-2,3-Benzoxazines
US4119777A (en) * 1975-12-23 1978-10-10 Fuji Photo Film Co., Ltd. Thiazine production
US4132436A (en) * 1976-02-04 1979-01-02 Fuji Photo Film Co., Ltd. Recording material
US4164407A (en) * 1977-10-07 1979-08-14 Sandoz, Inc. Benzoxazine herbicides
US4214889A (en) * 1977-10-07 1980-07-29 Sandoz, Inc. Benzoxazine herbicides
US4533379A (en) * 1982-06-25 1985-08-06 Shell Oil Company Herbicidal urea compounds

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2625798B1 (fr) * 1988-01-08 1990-07-06 Perez Benoit Ballon de production d'eau chaude et procede de mise en chauffe dudit ballon

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3168517A (en) * 1965-02-02 Novel z-phenylamino-x

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3168517A (en) * 1965-02-02 Novel z-phenylamino-x

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3725404A (en) * 1966-11-24 1973-04-03 Hoechst Ag 2-amino-4,4-di-substituted-4h-3,1-benzoxazines
US3502666A (en) * 1966-11-26 1970-03-24 Hoechst Ag 3,1-benzothiazine derivatives
US4005082A (en) * 1967-09-25 1977-01-25 Gruppo Lepetit S.P.A. 1H-2,3-Benzoxazines
US4002622A (en) * 1975-10-30 1977-01-11 Morton-Norwich Products, Inc. 2-(3-Chloroanilino)-4H-3,1-benzothiazine
US4002621A (en) * 1975-10-30 1977-01-11 Morton-Norwich Products, Inc. 6-Chloro-2-(3,4-dichloroanilino)-4H-3,1-benzothiazine
US4002620A (en) * 1975-10-30 1977-01-11 Morton-Norwich Products, Inc. 2-Anilino-4H-3,1-benzothiazines
US4119777A (en) * 1975-12-23 1978-10-10 Fuji Photo Film Co., Ltd. Thiazine production
US4132436A (en) * 1976-02-04 1979-01-02 Fuji Photo Film Co., Ltd. Recording material
US4164407A (en) * 1977-10-07 1979-08-14 Sandoz, Inc. Benzoxazine herbicides
US4214889A (en) * 1977-10-07 1980-07-29 Sandoz, Inc. Benzoxazine herbicides
US4533379A (en) * 1982-06-25 1985-08-06 Shell Oil Company Herbicidal urea compounds

Also Published As

Publication number Publication date
ES327432A1 (es) 1967-10-16
DE1545820A1 (de) 1969-12-11
BR6680180D0 (pt) 1973-12-26
DE1670677A1 (de) 1970-05-06
CH496724A (de) 1970-09-30
DE1670679A1 (de) 1970-08-06
NO119681B (en)) 1970-06-22
FR5709M (en)) 1968-01-15
DE1670680A1 (de) 1970-06-11
DE1670679B2 (de) 1973-03-22
IL25858A (en) 1971-01-28
DE1670679C3 (de) 1973-10-18
NL6607386A (en)) 1966-12-05
GB1152486A (en) 1969-05-21
BE682070A (en)) 1966-12-05
FR5710M (en)) 1968-01-15
DE1670681A1 (de) 1970-08-20

Similar Documents

Publication Publication Date Title
US3417085A (en) 3,1-benzothiazines and 3,1-benzoxazines
CA1121820A (en) Quinazoline compounds
US4171363A (en) 1,2,3-Thiadiazole process
US3725404A (en) 2-amino-4,4-di-substituted-4h-3,1-benzoxazines
US3227713A (en) Azine derivatives
WO1999007672A1 (en) Derivatives of 2,5- and 3,5-disubstituted anilines, their preparation and use
EP2161266A1 (en) Benzofuran derivatives as orexin receptor antagonists
US3235551A (en) Novel derivatives of
US2852510A (en) Heterocyclic compounds and process for producing same
FI64144C (fi) Foerfarande foer framstaellning av 2-arylamino-2-imidazolinderivat
PT97700B (pt) Processo de preparacao de agentes terapeuticos anti-diabeticos
US3538086A (en) 4-oxo-4h-pyrimido 2,1-b benzothiazoles
WO2004000322A1 (en) Thiazine and oxazine derivatives as mmp-13 inhibitors for treating arthritis
Cain et al. Potential antitumor agents. 23. 4'-(9-Acridinylamino) alkanesulfonanilide congeners bearing hydrophilic functionality
US3966950A (en) Novel therapeutic compositions and method involving thiazol-carboxamides
US3574212A (en) Quinazolinylureas
CA1312870C (en) Alkanesulfonamides as antiglaucoma agents
US3318882A (en) 2-amino-5-diloweralkyl sulfamoyl-n, n-disubstituted benzamides
US3752818A (en) Sulphonyl ureas and sulphonyl semicarbazides containing heterocyclic acyl amino groups and their production
GB1597811A (en) Benzothiadiazine derivatives
US4083979A (en) Thiazolidine derivatives and their use as salidiuretics
US3979397A (en) Pharmaceutically effective novel 3,4-dihydro-1,2- and 1,3-thiozolo [4,3a] is
DD232045A5 (de) Verfahren zur herstellung von vorwirkstoffen entzuendungshemmender oxicame
US3717637A (en) TRIFLUOROMETHYLTHIO SUBSTITUTED DIBENZ [b,f] [1,4] OXAZEPINES
US3574194A (en) 1-alpha-ethyl - alpha - methyl-succinimido) -4-sulphonamidobenzene and related compounds